Familial and Hereditary Colon Cancer Aasma Shaukat, MD, MPH, FACG, FASGE, FACP GI Section Chief, Minneapolis VAMC Associate Professor, Division of Gastroenterology, Department of Medicine, University of Minnesota The Causes of CRC ~15% Familial ~75% Sporadic ~5% HNPCC ~1% FAP ~1% IBD ~1% MAP ~1% Hamartomas 1
Hereditary Colorectal Cancer Syndromes Familial Adenomatous Polyposis (FAP) MYH-Associated Polyposis (MAP) Hereditary Nonpolyposis Colorectal Cancer/ Lynch Syndrome (HNPCC) Hamartomatous Polyposis Syndromes: Peutz-Jeghers Syndrome (PJS) Juvenile Polyposis Syndrome (JPS) Cowden s Syndrome How does knowledge of molecular pathways influence care of my patients? Identify high risk groups Estimate risk of cancer Understand cancer phenotype Know about risk of associated cancers Know which family members to test and when 2
Lifetime Risk of CRC 20-30% 70-80% >95% Lifetime Risk of CRC (%) Classification of Cancer-Causing Genes Tumor Suppressor Genes Are inhibitors of cell growth ( brakes ) If mutated, can contribute to cancer development Oncogenes When activated, can accelerate cell growth ( gas pedal ) and contribute to tumor development. 3
Classification of mutations Somatic Acquired Not heritable Only detected in tumor tissue Germline Inherited Heritable Can be detected in every pluripotent cell of the body Don t always lead to cancers Genes Implicated in Hereditary Colorectal Cancer Syndromes Syndrome Gene Chrom Function FAP APC 5q21-22 Gatekeeper HNPCC MSH2 2p21-2 Caretaker ; HNPCC MLH1 3p21.3 DNA MMR HNPCC PMS2 7p22 HNPCC PMS1 2q31-33 PJS STK11 19q13.3 Protein kinase JPS PTEN 10q23.3 Landscaper ; Phosphatase JPS DPC4/ 18q21.1 Landscaper ; SMAD4 TGFβ1 signaling 4
The Genetic Paradigm of CRC Formation APC COX-2 overexpression K-RAS DCC/DPC4 p53 Normal Epithelium Dysplastic ACF Early Adenoma Intermediate Adenoma Late Adenoma Carcinoma MSH2, MLH1, PMS2, etc. Case 1 A 35 yo male presents with rectal bleeding. Colonoscopy shows 100+ polyps, mostly in the left colon, majority are <1cm, a few 1-2 cm 1. What are the differential diagnoses? 2. What is the optimal management? 3. What others tests would you recommend? 4. What genetic tests would you order? 5. What are the recommendations for his children? 5
Familial Adenomatous Polyposis (FAP) Autosomal dominant Germ-line mutation in the APC gene located on 5q21-22 Occurrence: ~ 1 in 8,000 live births Characterized by multiple (>100) adenoma in the colon beginning around 15 years of age Colon cancer develops around 35 years of age FAP Endoscopic Findings 6
Extra colonic manifestations of FAP Duodenal and peri-ampullary adenomas and adenocarcinoma Pigmented lesion on retina (CHRPE) Desmoid tumors Sebaceous cysts Osteoma Gardner s syndrome: combination of Polyposis, osteoma, sebacous cyst or fibroma APC Gene Mutations More than 300 mutations in APC identified, most of which cause truncation of the protein Mutations between codons 169-1393 cause classical FAP Mutations towards N or C terminus of the protein cause attenuated FAP 7
The APC (Adenomatous Polyposis Coli) Gene 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Exon Classic FAP Attenuated FAP Screening for other cancers in FAP Starting at age 30-35 years: Upper GI endoscopy with a side-viewing endoscope q 1-3 years Endoscopic ultrasound of suspicious lesions at ampulla Sample gastric fundic gland polyps if large +/- Annual thyroid ultrasound Gallagher MC et al. Surveillance and management of upper gastrointestinal diseases in familial adenomatous polyposis. Fam Cancer 2006;5:263-73; Herraiz M et al. Prevalence of thyroid cancer in FAP and role of screening ultrasound. Clin Gastroentrol Hepatol 2007;5:367-373 8
Case 1: A 35 yo male presents with rectal bleeding. Colonoscopy shows 100+ polyps, mostly <1cm, a few 1.5-2 cm 1. What are the D/Dx? 2. What is surgical management? 3. What others tests would you recommend? 4.What genetic tests would you order? 1. D/Dx: FAP, MAP, hamartomatous polyposis 2. Total colectomy with IPAA 3. EGD w side-viewing scope +/- biopsy of ampulla 4. Germline testing for mutations in APC, MYH Screening Guidelines - Family History of FAP Genetic counseling Genetic testing ti A negative genetic test result rules out FAP only if an affected family member has an identified mutation Gene carriers or indeterminate cases should be offered flexible sigmoidoscopy id every 12 months beginning at puberty If polyposis is present, consider colectomy 9
Case 2 45 year old male undergoes colonoscopy for hematochezia. There are 30-40 polyps throughout the colon, ten of which are removed. Histology shows adenomas. What is your differential diagnosis? What is appropriate management? Attenuated FAP 10-100100 adenomatous polyps throughout the colon Similar lifetime risk of CRC as FAP, but may occur at later age than person with classical FAP 10
Case 2: 45 yo male with 30-40 adenomas What is your differential diagnosis? AFAP, MAP What is appropriate management? Detailed family history, genetic counseling and testing MYH-Associated Polyposis (MAP) Is found in a small number of suspected FAP patients with no identifiable APC mutations. Autosomal recessive Germ-line mutations in both alleles of MYH, which is involved in base excision repair (BER) Tumors contain somatic mutations in the APC gene 11
MYH associated polyposis Autosomal dominant (FAP) Autosomal recessive (MAP) CRC CRC CRC CRC Case 3: 35 yo female with cecal carcinoma and no other polyps. Mother had endometrial cancer at age 50 Is there a genetic predisposition to cancer? What are the differential diagnoses? Would you recommend testing tumor vs. germline testing? What genes would you test t for? What other tests does she need? When should the next colonoscopy be? 12
Hereditary Nonpolyposis Colon Cancer (HNPCC) Autosomal dominant. Occurrence: 1 in 1,000 live births. Germ-line mutations in one of the DNA mismatch repair (MMR) genes, leading to a microsatellite instability (MSI) phenotype 80% affected individuals will develop CRC Average age of onset of CRC: 44 years HNPCC Oligopolyposis: Few/ scant /no polyps! Polyp: Cancer ratio is 1:1 or 1:2 Rt sided, mucin-rich, poorly diff tumors, good prognosis Increased risk of extracolonic malignancies: Renal, ovarian, small bowel, endometrial, biliary, pancreatic, brain, stomach 2 nd most common cancer site is endometrial 13
Genes Mutated in HNPCC Mismatch Repair (MMR) Genes 25% unknown 5% PMS 1/2 MSH2 30% MSH6 10% MLH1 30% Amsterdam Criteria for the Diagnosis of HNPCC - The 3-2-1 Rule Three or more relatives with CRC, one of whom is a 1 st degree relative of the other 2, Two or more generations with CRC, One or more CRC case diagnosed before age 50. 14
Revised Bethesda Guidelines CRC under age 50 Synchronous or metachronous CRC or HNPCC-associated tumor CRC with one or more FDR with CRC or HNPCC tumor, one less than 50 CRC with 2 or more FDR relatives with CRC or other HNPCC tumors, any age Guidelines on genetic evaluation and management of Lynch syndrome: A consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer Giardiello FM et al. Gastrointestinal Endoscopy Volume 80, Issue 2, Pages 197-220 (August 2014) 15
Surveillance recommendations for HNPCC patients Colonoscopy beginning age 20-2525 repeat q 1-2 yrs TV US and endometrial aspirate annually starting age 25-35 Long-term use of aspirin may reduce risk of cancer Burn J et al. Aspirin prevents cancer in Lynch syndrome. Eur J Cancer 2009;7:320-21 Case 3: 35 yo female with cecal carcinoma and no other polyps. Mother had endometrial cancer at age 50 1. Is there a genetic 1. Likely ey predisposition to cancer? 2. What are the D/Dx? 3. Would you recommend testing tumor vs. germline testing? 4. What genes would you test for? 5. What other tests does she need? 6. When should the next colonoscopy be? 2. HNPCC, Sporadic CRC 3. Tumor: IHC and MSI testing. If NA or positive then germline 4. MLH1, MSH2, MSH6 5. TV US and Endometrial bx 6. 1-2 years 16
IHC for Tumor tissue for MLH1, MSH2 HNPCC suspected: MSI testing of tumor DNA: Panel of 7 mono and dinucleotide sequences. >40% instability: MSI + + Germline DNA for mutations in MLH1 MSH2 Universal molecular testing for Lynch? Likely to be standard in the future 28% of Lynch syndrome patents missed with the most sensitive revised Bethesda criteria Endorsed by recent MSTF for all patients with CRC <70 years of age when appropriate infrastructure exists Giardiello FM et al. Gastrointestinal Endoscopy Volume 80, Issue 2, Pages 197-220 (August 2014) 17
Universal screening by tumor testing IHC for Tumor tissue for MLH1, MSH2 CRC + MSI testing of tumor DNA - + + Loss of other MMR proteins Loss of MLH1 or PMS2 NO further testing + BRAF testing - GENETIC COUNSELLING Giardiello FM et al. Gastrointestinal Endoscopy Volume 80, Issue 2, Pages 197-220 (August 2014) Sensitivity for diagnosis of Lynch syndrome Test Amsterdam Criteria Bethesda Criteria IHC for MLH1 MSH2 PMS2 MSH6 Tumor tissue MSI testing PREMM Sensitivity 22% 98% 82% 77% 83% 89% 85% 90% 90% 67% Specificity 18
Genetic counseling Indication: Amsterdam criteria Bethesda Criteria Uterine cancer < 50y Known Lynch syndrome in family >5% chance of mutation by prediction models Counseling: Family history evaluation Education Risk assessment Management recommendations Informed consent for genetic testing Genetic testing and interpretation of results Familial Colorectal cancer type X 40-70% of Amsterdam-positive cases do not have MMR CRC risk is lower than Lynch syndrome and occurs10 years later Yet to be identified genes type X Familial cancers: 20% of all CRC occur in individuals with a FDR less than 50 with CRC or two FDR: several common loci of low penetrance genes 19
What is Genetic Discrimination? Social or economic discrimination based on ones hereditary predisposition to disease Denial of access to or increased cost of insurance Loss of employment, educational or other opportunities No data to support genetic discrimination i i occurs in relation to testing for cancer predisposition Genetic Malpractice Failure to make a diagnosis and use proper diagnostic tools Failure to recommend adequately aggressive cancer surveillance Failure to recommend surveillance or prophylactic surgery for associated cancers Failure of duty to warn family members HIPAA protects you! 20
Conclusions Enormous progress has been made in understanding the genetic basis of CRC Ongoing research continues to show new mechanisms of CRC tumorigenesis A relatively large proportion of familial CRC cases still do not have a definitive genetic etiology Genetic testing are available for many hereditary CRC syndromes but require careful interpretation of results 21